1. AlzheimerAlzheimer’’s Disease Risk Genes Disease Risk Gene CD33CD33
Inhibits Microglial Uptake of Amyloid BetaInhibits Microglial Uptake of Amyloid Beta
Ana Griciuc, Ph.D.Ana Griciuc, Ph.D.
Massachusetts General HospitalMassachusetts General Hospital
Harvard Medical SchoolHarvard Medical School

2. Alzheimer’s Disease Risk Gene CD33
Inhibits Microglial Uptake of Amyloid Beta
Research in the Tanzi Laboratory
Discovery
Genetics of familial and late-onset AD
Mutations in APP, PS1, PS2 linked to FAD
UBQLN1, ADAM10, ATXN1 and CD33 genes linked to LOAD
Basic and pre-clinical research
Novel animal and in vitro models of AD
Molecular mechanisms of brain aging and AD
Novel therapies: γ-secretase modulators, metal chelators
Clinical research collaborations
Several compounds currently in clinical trials

3. CD33 is a Novel Risk Factor for LOAD
The minor “G” allele of the
rs3826656 is a risk allele (Bertram
et al., 2008)
The minor “T” allele of the
rs3865444 is protective (Naj et al.,
2011; Hollingworth et al., 2011)
CD33 is activated by sialic acids,
and regulates inflammatory
responses of the innate immune
system

4. Increased Numbers of CD33-positive Microglia in AD
CD33
CD33
Iba1
Iba1
CD33/Iba1/DAPI
CD33/Iba1/DAPI
CTRLAD
CD33
CD33
CD33+
microglia/mm2
Aβplaqueburden(%) r=0.471
p=0.017
0
40
80
120
**
CD33+
microglia/mm2
G/G G/T T/T
CD33+
microglia/mm2
CTRL AD
***

5. Decreased Numbers of CD33-Immunoreactive Microglia
in Carriers of the Minor Protective Allele “T” of rs3865444
CD33 Localizes Around the Core of Amyloid
Plaques in AD Brain
ThioS CD33 ThioS/CD33 Iba1
ThioS CD33 ThioS/CD33 Iba1

6. WTCD33-/-
CD33
CD33 Aβ42
Aβ42
CD33/Aβ42
CD33/Aβ42
Iba1
Iba1
CD33 Inactivation Promotes the Uptake of Amyloid Beta
by Microglia
CD33-/-
WT
0
1
2
3
InternalizedAβ42(a.u.)
**

7. CD33 inhibits microglial uptake of amyloid beta
CD33-mediated Inhibition of Amyloid Beta Uptake by
Microglia Requires Sialic Acid Binding
Inhibition
of Amyloid Beta Uptake
No Inhibition
of Amyloid Beta Uptake
CD33 Aβ42
CD33 Aβ42
CD33 Aβ42
EmptyvectorCD33WTCD33ΔV-Ig
CD33/Aβ42
CD33/Aβ42
CD33/Aβ42

8. CD33 Inactivation Mitigates Amyloid Beta Plaque
Pathology in APP/PS1 Mice
APP/PS1 APP/PS1/CD33‐/‐
APP/PS1 (n=11)
APP/PS1/CD33-/-
(n=9)
0
0.2
0.4
0.6
0.8
Aβplaqueburden(%)
Cortex
**
CortexHippocampus
Aβplaqueburden(%)
Hippocampus
*
0
0.1
0.2
0.3
0.4

9. Conclusions
CD33 activity in microglial cells strongly impairs their ability to
clear brain amyloid.
Novel pathway linking CD33 activity in microglial cells to
amyloid accumulation in the aging brain.
Targeting CD33 activity might delay or arrest cognitive decline
and AD?

10. Rudy TanziRudy Tanzi
SeSe HoonHoon ChoiChoi
AndreaAndrea LesinskiLesinski
CarolineCaroline AsselinAsselin
TonyTony ParradoParrado
Kristina MullinKristina Mullin
RajRaj HooliHooli
JaehongJaehong SuhSuh
Can ZhangCan Zhang
ZhongcongZhongcong XieXie
Bradley HymanBradley Hyman -- MGH/HarvardMGH/Harvard
Alberto SerranoAlberto Serrano--PozoPozo -- MGH/HarvardMGH/Harvard
Lars BertramLars Bertram -- Max PlanckMax Planck
Cure AlzheimerCure Alzheimer’’s Funds Fund
National Institutes of HealthNational Institutes of Health
Deutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft
ACKNOWLEDGEMENTSACKNOWLEDGEMENTS
THANK YOU!THANK YOU!